The invention relates generally to bicyclic carbohydrate compounds useful in the treatment of infections caused by Flaviviridae sp. and, more specifically, to such compounds useful in the treatment or amelioration of infections caused by hepatitis C, bovine viral diarrhea, classical swine fever, West Nile and dengue viruses.
Hepatitis C was first recognized as a separate disease entity in 1975 when the majority of cases of transfusion-associated hepatitis were found not to be caused by the only two hepatitis viruses recognized at the time, hepatitis A virus and hepatitis B virus. The disease was called “non-A non-B hepatitis,” and it was demonstrated to be transmissible to chimpanzees. It was not until 1989, however, that the cloning and sequencing of the viral genome of the non-A non-B hepatitis virus was first reported and the virus was renamed “hepatitis C virus” (HCV). Tests for antibody to HCV quickly followed, and screening for such antibody remains a principal method of diagnosis.
Hepatitis C virus shares virological and genetic characteristics with the Flaviviridae. Its genomic organization is similar to that of the flaviviruses and pestiviruses and shares slight sequence identity with these viruses, especially the pestiviruses. Each of these groups of viruses comprises a separate genus within the Flaviviridae: flavivirus, pestivirus and hepacivirus. Hepatitis C virus is a spherical enveloped virus of approximately 50 nm in diameter. The genome of HCV is a single-strand linear RNA of positive sense. It is unsegrnented. A 5′ non-coding (NC) region consists of approximately 340 nucleotides. Immediately downstream is a single large open reading frame (ORF) of approximately 9000 nucleotides. Finally there is a 3′ NC region that consists of approximately 100 nucleotides. The genome of HCV is highly heterogeneous. The most highly conserved regions of the genome are parts of the 5′ NC region and the terminal 3′ NC region. The most highly conserved region of the ORF is the capsid gene. In contrast, the most heterogeneous portions of the genome are the genes encoding the envelope proteins. Based on their genetic heterogeneity, HCV strains can be divided into major groups, called types or genotypes (and provisionally classified as separate species) of the virus. Within types, HCV isolates have been grouped into numerous subtypes. Finally, individual isolates consist of heterogeneous populations of the viral genomes that comprise “quasispecies” or “swarms” of closely related but different viruses. Some genotypes of HCV appear to be geographically restricted; others have worldwide distribution. More extensive genetic analysis of HCV has revealed that the hierarchical classification of isolates into types, subtypes, and isolates is somewhat artifactual and the viruses probably exist as a continuum of genetic diversity. The consequence of the genetic diversity of HCV is a virus that has the ability to escape the immune surveillance of its host, leading to a high rate (more than 80 percent) of chronic infections and lack of immunity to re-infection in repeatedly exposed individuals. Both chronicity and lack of solid immunity probably result from the emergence of minor populations of the virus quasispecies that vary in sequence (www.HEPNET.com, the Hepatitis Information Network; Challand R., Young R. J. (1997) Antiviral Chemotherapy. Biochemical & Medicinal Chemistry Series. Spektrum Academic Publishers, Oxford, pp. 87–92; Cann A. J. (1997) Principles of Molecular Virology. Second Edition. Academic Press, San Diego, pp. 230–235). Other important Flaviviridae that give rise to medical unmet needs are West Nile virus and the virus causing dengue.
Therefore, a strong medical need exists to discover and develop new bioactive molecules that can be used to treat Flaviviridae infections with fewer or reduced side effects and better efficiency compared to the current available treatments.